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Park, Chan Young
Calcium Dynamics Lab
Research Interests
  • Calcium Signaling, Calcium Channels, Immune, neuroscience, Drug Development, Virus and host cell interaction.

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Identification of Orai1 channel inhibitors by using minimal functional domains to screen small molecule microarrays

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Title
Identification of Orai1 channel inhibitors by using minimal functional domains to screen small molecule microarrays
Author
Sadaghiani, Amir Masoud SadaghianiLee, Sang MinOdegaard, Justin I.Leveson-Gower, Dennis B.McPherson, Olivia M.Novick, PaulKim, Mi RiKoehler, Angela N.Negrin, RobertDolmetsch, Ricardo E.Park, Chan Young
Issue Date
2014-10
Publisher
CELL PRESS
Citation
CHEMISTRY & BIOLOGY, v.21, no.10, pp.1278 - 1292
Abstract
Store-operated calcium (SOC) channels are vital for activation of the immune cells, and mutations in the channel result in severe combined immunodeficiency in human patients. In lymphocytes, SOC entry is mediated by the Orai1 channel, which is activated by direct binding of STIM1. Here we describe an alternative approach for identifying inhibitors of SOC entry using minimal functional domains of STIM1 and Orai1 to screen a small-molecule microarray. This screen identified AnCoA4, which inhibits SOC entry at submicromolar concentrations and blocks T cell activation in vitro and in vivo. Biophysical studies revealed that AnCoA4 binds to the C terminus of Orai1, directly inhibiting calcium influx through the channel and also reducing binding of STIM1. AnCoA4, unlike other reported SOC inhibitors, is a molecule with a known binding site and mechanism of action. These studies also provide proof of principle for an approach to ion channel drug discovery.
URI
https://scholarworks.unist.ac.kr/handle/201301/8606
URL
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84908337125
DOI
10.1016/j.chembiol.2014.08.016
ISSN
1074-5521
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